DNA has been obtained from approximately 20 major malformations for current and future investigations. We have recently expanded our investigations to include searching for copy number variants in rare defects. New York has an exceptionally valuable research resource in having approximately 250,000 births per year from which to identify children with rare defects. In addition to classic candidate gene approaches, cases have been selected for copy number variant studies. The laboratory work has now been completed on many of the conditions selected for copy number variant testing. Copy number variants have been identified in several conditions of interest. We have completed our investigation of heterotaxy-associated copy number variants; written up the results; and they have been accepted for publication in Genetics in Medicine. We are analyzing the copy number data in other conditions including Klippel Trenaunay syndrome, prune belly syndrome, posterior urethral valves, hypoplastic right heart, and Ebstein's anomaly. In the past year, we have expanded our collaboration with The California Department of Health and Stanford Universiy. We have completed the first laboratory work on samples from California, examining copy number variants in heterotaxy cases. The analysis will begin shortly. Additional samples from California will be obtained to look at other congenital heart defects. We are in the process of getting approval to use samples from the California repositories to conduct research on other rare, non-cardiac defects. We have also collaborated with large groups doing genome wide association studies. Our work on idiopathic hypertrophic pyloric stenosis (IHPS) is noteworthy. IHPS is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited. We collaborated with investigators in Denmark and Sweden to conduct a genome-wide search for candidate genes. We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. The single-nucleotide polymorphism (SNP) with the lowest P value at the locus, rs12721025 (odds ratio OR, 1.59; 95% CI, 1.38-1.83; P=1.9x10(-10)), is located 301 bases downstream of the apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol-lowering allele consistently was associated with increased risk of IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk, which warrants further investigation. We raise the speculative hypothesis that cholesterol may be involved in the causation of IPHS as a possibility that merits investigation. These findings have been published in JAMA. We are expanding our work on pyloric stenosis to include other genes. We have initiated new collaboration with the CDC's National Birth Defects Prevention Study. In conjunction with Dr. Paul Romitti at the University of Iowa, we will be searching for genetic factors associated with choanal atresia, a defect in which the nasal passages fail to develop normally. This study involves testing samples from New York State and from the collaborative group that formed the National Birth Defects Prevention Study. We will be collaborating with another consortium following up on our work described in last year's report on craniosynostosis (see Justice et al. Nature Genetics). The previous work focused on saggital craniosynostosis. The future work will expand on this to look for genetic factors associated with defects in other sutures.